1. Field of the Invention
The present invention is directed to intermediates which can be converted into podophyllotoxin and related compounds, which are known antineoplastic agents. Additionally, the present invention provides processes for the preparation of such intermediates, and processes for the conversion of the intermediates into known intermediates which are readily converted into podophyllotoxin and related compounds.
2. Description of the Prior Art
Podophyllotoxin (I), a known lignan lactone isolated from several species of Podophyllum, is a potent cytotoxic agent. Numerous other related compounds having the characteristic aryltetralin ring structure, either naturally occurring or derived from some naturally occurring compounds are known. Some of these compounds possess antineoplastic activity while others are useful for conversion to compounds having such activity. Podophyllotoxin has the structure shown below: ##STR4##
Podophyllotoxin has also been prepared synthetically. The synthesis involves the production of picropodophyllin (II), shown below: ##STR5## Picropodophyllin is the cis-lactone isomer of podophyllotoxin (I), and can be epimerized into podophyllotoxin (I) according to the procedure of Gensler et al, described in J. Org. Chem., 31, 404-8 (1966). The epimerization is accomplished by preparing the O-tetrahydropyranyl derivative of picropodophyllin, converting it to the sodium enolate by treatment with triphenylmethylsodium, and quenching the enolate with excess acetic acid.
In J. Am. Chem. Soc., 82, 1714-1727 (1960), Gensler et al report the total synthesis of picropodophyllin (II) by a lengthy procedure involving 14 steps and a low overall yield.
More recently, in U.S. Patent No. 4,122,092 to Andrew S. Kende and Peter S. Rutledge, there has been described a simpler, more direct route for the production of picropodophyllin (II) involving, as an intermediate, a tetralone of formula III, (their XV), shown below: ##STR6## wherein R.sup.2 is alkyl and R is methyl or hydrogen. Compound III is produced by a four-step procedure utilizing 2-(3,4-methylenedioxyphenyl)ethyl mesylate as a starting material, wherein the immediate precursor to the tetralone III is the corresponding tetralin. However, oxidation of the tetralin to the tetralone III cannot readily be achieved on a larger than 0.2 g. scale and thus presents a volumetric limitation to the synthesis. Conversion of the tetralone III to picropodophyllin (II) is thereafter readily accomplished by the four-step procedure disclosed in the above-cited Kende et al patent.
U.S. Pat. No. 3,524,844 to Keller-Juslen et al discloses 4'-demethylepipodophyllotoxin-.beta.-D-(substituted) glucosides of the formula: ##STR7## wherein, inter alia, R.sup.1 is hydrogen and R.sup.2 is an alkyl or a 2-thienyl moiety. These compounds are prepared from 4'-demethylepipodophyllotoxin V shown below: ##STR8## which, in turn, is prepared from podophyllotoxin. Both of the latter conversions are described in U.S. Pat. No. 3,524,844. The 4'-demethylepidophyllotoxin-.beta.-D(substituted)-glucosides are antineoplastic agents.